Immunoglobulin E (IgE) mediates type-I hypersensitivity reactions responsible for human allergic diseases such as asthma, hay fever, and food and drug allergies. IgE circulates in the blood, and binds to high affinity IgE Fc specific receptors (Fc.sub..epsilon. R-I) on the surface of mast cells and basophils. In an IgE-mediated response, multivalent allergen crosslinks Fc.sub..epsilon. R-I bound IgE on mast cells and basophils, thereby aggregates the underlying receptors and triggers the release of histamine and other vasoactive pharmacological mediators.
The treatment of IgE-mediated diseases has involved various approaches including the avoidance of offending allergens, the pharmacological therapy of symptoms and repeated injection of allergen in hyposensitization regimens. Frick, O. L. 1982. "Immediate hypersentivitiy." In Basic and Clinical Immunology, eds. Stites, D. P., Stobo, J. D. and Wells, J. V., Lange Medical Publications, Los Altos, Calif., pg 250. Other therapeutic strategies include the blockage of high affinity IgE Fc receptors and the inhibition of binding onto mast cells and basophils.
Fragments and synthetic peptides of the IgE Fc region have been proposed as competitive inhibitors of IgE binding to the high affinity receptor. (Hamburger, R. N. 1975. "Peptide inhibition of Prausnitz-Kustner reaction." Science 117:314-322; Stanworth, D. R., Burt, D. S. 1986. "Anti-E chain antibodies as probes in the study of mast cell triggering." Mol. Immunol. 23:1231. However, presumably due to the much lower affinity of these peptides compared with whole IgE for the Fc.sub..epsilon. R, such peptides have not proven effcacious in blocking IgE binding onto the receptor.
Alternative strategies have been proposed which involve the modulation or down-regulation of IgE synthesis. Experimentally, IgE synthesis can be suppressed with T cell-derived IgE binding factors (Ishizaka K. 1984. "Regulation of IgE synthesis." Ann. Rev. Immunol. 2:195; Massicot J. G., Ishizaka, K. 1986. "Workshop on measurement of in vitro IgE synthesis and regulation of IgE synthesis." J. Allergy Clin. Immunol. 77:544-552.) Direct blockage of interleukin 4 (IL4) binding to its receptor might reduce IL4-induced B cell isotype switching to IgE and thus reduce IgE synthesis.
In earlier patent applications, U.S. Ser. Nos. 07/291,068, filed Dec. 28, 1988 (now abandoned) and U.S. Pat. No. 5,091,313, filed Nov. 16, 1988, the discovery of unique epitopes on B cell bound IgE, and of monoclonal antibodies that bind to IgE on B cells but not basophils and the various applications of these monoclonal antibodies in the treatment of patients with allergic diseases were described. The pharmacologic mechanism of therapies based on those antibodies is to target and to lyse IgE-producing B cells to decrease the synthesis of IgE.